Biliary innate immunity and cholangiopathy
Biliary innate immunity and cholangiopathy
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DOI：
10.1111/j.1872-034x.2007.00247.x
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发表时间：
2007-10-01
影响因子：
4.2
通讯作者：
Nakanuma, Yasuni
中科院分区：
文献类型：
--
作者：
Harada, Kenichi;Nakanuma, Yasuni
肝内胆道树是胆汁的管道，其中含有病原体相关分子模式（PAMPs），如源自肠道菌群的脂多糖（LPS）。人胆道上皮细胞（BEC）表达toll样受体（TLR）和细胞内接头分子，并通过激活核转录因子分泌抗生素肽和促炎性细胞因子。然而，尽管人的胆汁在正常和患病肝脏中都含有几种PAMPs，但从生理上讲，PAMPs不会引起胆道树的炎症反应，这表明对包括内毒素耐受在内的共生PAMPs的耐受对于维持胆道先天免疫的稳态很重要。细胞内TLR信号的负调节因子，过氧化物酶体增殖物激活受体γ (ppar - γ)和IRAK-M，与BEC的内毒素耐受性有关。在体内，ppar - γ和IRAK-M在肝内胆道上皮中普遍表达，而ppar - γ在原发性胆汁性肝硬化（PBC）受损胆管中的表达减少。除了抗生素肽外，BEC还作为先天免疫反应分泌多种细胞因子和趋化因子，这些体液成分参与吸引免疫细胞和调节胆道周围细胞因子环境。BEC具有多种细胞因子受体，TLR在BEC中的表达受细胞因子的影响，提示胆道先天免疫受获得性免疫调节。t辅助（Th）1型细胞因子干扰素- γ下调ppar - γ，上调TLR，从而增加胆道先天免疫的易感性。由于PBC中管周细胞因子环境以th1为主，PBC中pamp易感性的增加可能与胆管病变的发生有关。胆道先天免疫被推测与胆道疾病的发病机制以及对胆道微生物感染的防御有关。
The intrahepatic biliary tree is a conduit of bile which contains pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) originated from intestinal flora. Human biliary epithelial cells (BEC) express toll-like receptors (TLR) and intracellular adaptor molecules and secrete antibiotic peptides and (pro)inflammatory cytokines via the activation of nuclear transcription factors. However, although human bile contains several PAMPs in normal as well as diseased livers, PAMPs physiologically do not elicit an inflammatory response in the biliary tree, suggesting that tolerance against commensal PAMPs including LPS (endotoxin tolerance) is important in maintaining the homeostasis of biliary innate immunity. Negative regulators of intracellular TLR signalings, peroxisome proliferator activating receptor-gamma (PPAR-gamma) and IRAK-M, are associated with the endotoxin tolerance in BEC. In vivo, PPAR-gamma and IRAK-M are ubiquitously expressed in intrahepatic biliary epithelium, while the expression of PPAR-gamma is reduced in damaged bile ducts of primary biliary cirrhosis (PBC). In addition to antibiotic peptides, several cytokines andchemokines are also secreted from BEC as an innate immune response and these humoral components participate in attracting immunocytes and modulating peribiliary cytokine milieu. BEC have receptors for several cytokines and the expression of TLR in BEC is affected by cytokines, suggesting that biliary innate immunity is regulated by an acquired immunity. A T-helper (Th)1-type cytokine, interferon-gamma, downregulates PPAR-gamma and upregulates TLR, and consequently increases the susceptibility of biliary innate immunity. Because periductal cytokine milieu in PBC is Th1-dominant, the increased susceptibility to PAMPs may be associated with the development of cholangiopathy in PBC. Biliary innate immunity is speculated to be associated with the pathogenesis of biliary diseases as well as the defense against biliary microbial infection.